4902
(14)
(15)
(16) (17)
(18)
(19)
(20)
/ I00:15 / July 19, 1978
Journal of the American Chemical Society
(1962)). In analogous, separate incubations of mevalonate with d-1 and I-1 the yields of squalene 2,3-oxide were 16 and 14% and the yields of squalene 2,3:22,23dioxide were 14 and 11% . Both squalene 2,3-oxide and squalene 2,3:22,23dioxide are reported by E. J. Corey, P. R. Ortiz de Montellano, K. Lin, and P. D. G. Dean, J. Am. Chem. Soc., 89, 2797 (1967), to accumulate when 2,3-iminosqualene is used as an inhibitor. CHO cells possess intact cholesterol biosynthetic capacity: (a)T. Y. Chang and P. R. Vagelos. Roc. NatI. Acad. Sci. U.S.A., 73, 24 (1976): (b) T. Y. Chang, C. Telakowski, W. Vanden Heuvel. A. W. Alberts, and P. R. Vagelos, ibid., 74, 832 (1977). A. S. Kandutsch and H. W. Chen. J. Bo/. Chem., 249, 6057 (1974). TLC of the product obtained from this [14C acetate incorporation experiment yielded bands corresponding to /'*C]squalene 2,3-oxide and ['4C]squaiene 2,3:22,23-dioxide which contained 30 and 10%. respectively, of the total radioactivity in the nonsaponifiable fraction. Pertinent reviews: (a) W. L. Bencze, "Handbook of Experimental Pharmacology", Vol. 41, D. Kritchevsky, Ed.. Springer-Verlag. Berlin, 1975, p 349; (b) R. Howe, Adv. Drug Res., 9, 7 (1974); (c) W. Bencze, R. Hess, and G. de Stevens, Prog. Drug Res., 13, 217 (1969). Compound 3, reported as an oil by M. Yanagita and R. Futaki, J. Org. Chem., 21, 949 (1956). was isolated as a solid, mp 47-50 ' C (characterized by IR, NMR, and combustion analysis), from NaBH4 reduction of 4a,lOPdimethyCtrans-decaC3-one, obtained via Li/NHS reduction of 4,lOdimethyl-A4-decai-3-one, DreDared by. the method of N. C. Ross and R. Levine, ibid., 29, 2341 (1964). E. E. van Tamelen, A. D. Pedlar, E. Li, and D. R. James, J. Am. Chem. SOC., 99, 6778 (1977).
James A. Nelson,* Michael R. Czarny Thomas A. Spencer* Department of Chemistry, Dartmouth College Hanover, New Hampshire 03755 James S. Limanek, Keith R. McCrae, Ta Yuan Chang* Department of Biochemistry, Dartmouth Medical School Hanover. New Hampshire 03755 Received April 17, 1978
Sir: The [3,3] sigmatropic rearrangement of allyl vinyl ethers provides a versatile method for the construction of new carbon to carbon bonds with high regio- and stereospecificity under mild reaction conditions.2 Although the [3,3] sigmatropic rearrangement of allyl phenyl ethers is well examplified in the classic Claisen rearrar~gement,~ the [3,3] sigmatropic rearrangement of benzyl vinyl ethers 1 (W = H) is not generally
w
r
L
1
2
3
p ~ s s i b l eInspection .~ of the putative intermediate 2 suggested to us that the [3,3] sigmatropic rearrangement of 1 should be facilitated by an appropriately selected and suitably positioned substituent W.5,6 W e are now pleased to report that the reaction of ethyl mandelate derivatives 4 in the Claisen ortho ester rearrangement7J with 5 provides an extremely convenient method for FO,Et
CO,Et
+
RR'CHC(OR")~
+ X
X 4
(4)
entry a b C
d e f g h i l
ortho ester ( 5 ) R R' R"
mandelate (4), X H H H Me Me Me0
c1
CI EtO2C EtOL
H Me Me H Me H H Me H Me
reactiono % yieldb conditions of6
H E t H Et Me Et H E t H Et H Et H E t H Et H Et H Et
A B A B B C A B A B
84 50 41 65 47 50 30 21 33 18
All reactions use 6 to 8 equiv of 5 and 0.1 equiv of hexanoic acid/equiv of 4. The reaction flask is fitted with a 15-cm Vigreux column during the first time period and a short-path distillation head during the second time period (see sample experimental procedure). Reaction conditions: A, 1 2 h at 220 "C, 8 h at 185 "C; B, 12 h at 220 "C, 12 h at 185 "C; C, 5 h at 220 "C, 7 h at 185 "C. See ref 10.
Table 11. Claisen Ortho Ester Rearrangement with 3-Indoleglycolates ortho ester 5" R' R"
entry
indole 7, W
R
a b
C02Et C02Et CO2Et CONMe2 H
H H Me H H
C
d e
H H H H H
Et Me Et Me Me
% yieldb o f 8
79 48 40 59 d
a All reactions use 30 equiv of 5 and 0.1 equiv of hexanoic acid/ equiv of 4. The reaction flask was filtered with a 15-cm Vigreux column topped with a short-path distillation head and was heated at reflux for 12 h, the Vigreux column was removed, and heating was continued at 185 " C for 8 h. See ref 10. No ester exchange was detected. The corresponding mixed ortho ester was isolated (90%).
Regiospecific Synthesis of Substituted Arenes. [3,3] Sigmatropic Rearrangement of Benzyl Vinyl Ethers'
W
Table I. Claisen Ortho Ester Rearrangement of Ethyl Mandelates
5
the regiospecific synthesis of substituted arenes 6.9 The results of these studies are summarized in Table I.Io Several noteworthy features of the above transformation follow: (1) a large assortment of substituted ethyl mandelates 0002-7863/78/1500-4902$01 .OO/O
4lI and ortho esters 512are readily available; (2) the reaction occurs for ethyl mandelates with either electron-donating or electron-withdrawing groups; (3) the reaction conditions are compatible with a wide array of f ~ n c t i o n a l i t y(4) ; ~ ~the reaction provides a method for the regiospecific synthesis of substituted arenesI4 that would be difficulty accessible by alternative methods; and (5) the carboethoxy groups are convenient handles for subsequent synthetic transformations. W e have also extended this procedure to the Claisen ortho ester rearrangement of 5 with the 3-indoleglycolic acid derivatives 7 (W = C02Et or CONMez)'5,16to give 2,3-disubstituted indoles 817 (Table II).Io The crucial influence of the
7
8
carboxy derivative a t the benzylic position in facilitating the [3,3] sigmatropic rearrangement is again illustrated by experiments in which 1-tosyl-3-indolemethanol(7, W = H) failed to undergo any detectable rearrangement with trimethyl orthoacetate under comparable reaction conditions, but led only to the corresponding mixed ortho ester.I8 It is notable that the 2,3-disubstituted indoles 8 contain both a two-carbon functionalized chain a t the 3 position and an a-substituted carboxy group a t the 2 position. These features are present in a number of indole alkaloids such as vincadine, vindoline, carbomethoxyvelbanamine, and catharanthine. W e are currently investigating the application of the [3,3] sig-
0 1978 American Chemical Society
Communications t o the Editor
4903
matropic rearrangement of 3-indoleglycolic acid derivatives as the key step in a general scheme for the total synthesis of indole alkaloids; further investigations concerning the use of the [ 3,3] sigmatropic rearrangement for the regiospecific synthesis of other substituted arenes are also in progress.
Acknowledgment. This research was supported in part by an M. J. Murdock Charitable Trust Grant of Research Corporation, and by the University of Washington Graduate School Research Fund. References and Notes (1) Synthesis via Sigmatropic Rearrangements. 1. (2) For recent reviews, see (a) S. J. Rhoads and N. R. Raulins, Org. React., 22, 1 (1975); (b) F. E. Ziegler, Acc. Chem. Res., 10, 227 (1977); (c) G. B. Bennett, Synthesis, 589 (1977). (3) D. S. Tarbeil, Org. React., 2, l(1944). (4) For a discussion of the [3,3] sigmatropic rearrangement of benzyl vinyl ethers, see (a) G. B. Gill, 0.Rev. (London), 22,338 (1968). Thermal rearrangements of benzyl vinyl ethers generally occur via radical processes (i ii): (b) K. B. Wiberg. R. R. Kintner, and E. L. Motell, J. Am. Chem. SOC., 65, 450 (1963); (c) A. W. Burgstahler. L. K. Gibbons, and I. C. Nordin, J. Chem. Soc., 4986 (1963).Free-radical processes also occur in heterocyclic systems: (d) A. F. Thomas, Helv. Chim. Acta, 53, 605 (1970). The conversion of 1 to 3 where W = H and 2 = NMe2 is a notable exception: (e) +
i
ii
A. E. Wick, D. Felix, K. Steen, and A. Eschenmoser, ibid., 47, 2425 (1964); (f) D. Felix, K. Gschwend-Steen, A. E. Wick and A. Eschenmoser, ibid., 52, 1030 (1969). Benzyl &methylphenylacetate was obtained from ketene dibenzyl acetal, generated in situ by dehydrohalogenationof bromoacetaldehyde dibenzyl acetal: (9) S. M. McElvain, H. I. Anthes, and S. H. Shapiro, J. Am. Chem. SOC.. 64, 2525 (1942). For another exception, see (h) W. J. LeNoble. P. J. Crean, and B. Gabrielson, ibid., 86, 1649 (1964). (5) It is noteworthy that, when W = carbonyl, 2 is vinylogously related to the cyclohexadienone which is initially formed in the [3.3] sigmatropic rearrangement of allyl phenyl ethers. (6) For a recent example of the dramatic influence on a [3.3] sigmatropic rearrangement caused by an effective change in substituents (i.e., -OH -O-K+), see D. A. Evans and A. M. Golob, J. Am. Chem. Soc., 97,4765 (1975). (7) (a) W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brocksom, T.-T. Li, D. J. Faulkner, and M. R. Peterson, J. Am. Chem. SOC., 92,741 (1970). (b) As usual in the Claisen ortho ester rearrangement, we made no attempts to isolate the intermediate benzyl vinyl ether. (8) We have also effected Claisen rearrangement of ethyl mandelate with I-methoxycyclohexene to give Iii. +
@+6 \
iii
(9) In marked contrast, reaction of benzyl alcohol with triethyl orthoacetate, under the same conditions used for ethyl mandelate, gave predominantly benzyl diethyl orthoacetate accompanied by small amounts of ethyl 3phenylpropionate and ethyl mnethylphenylacetate (presumably via radical processes; cf. ref 4b-d). (IO) (a) A typical experimental procedure follows. A solution of ethyl mandelate (2.00 mmol), triethyl orthoacetate (16 mmol), and hexanoic acid (0.20 mmol) in a 50-mL flask fitted with a 15-cm Vigreux column topped with a shortpath distillation head was heated at 220 OC for 12 h in an argon atmosphere; ethanol was allowed to distil out of the reaction solution as It was formed. The Vigreux column was removed, the short-path distillation head was placed on the reaction flask, and heating was continued at 185 OC for 8 h. Excess ortho ester was removed (35 OC, 1 mm) and the residue was purified by chromatography on silica gel (30 g, hexane-ether eluent), followed by evaporative distillation (120 OC, 0.002 mm) to give diethyl o. benzenediacetate (sa) as a colorless liquid (210 mg, 64%): 'H NMR (CCI4) 6 1.15 (t, J = 7 HZ, 6 H), 3.60 (S.4 H, ArCHz-), 4.08(q, J = 7 Hz, 4H), 7.13 (s, 4 H); IR (neat) Y 1740 cm-'. Anal. (C14H1804) C, H, 0. Found m/e 250.1 196. (b) All new compounds were fully characterized by spectroscopic methods. Yields are given for isolated products purified by column chromatography (silica gel) followed by evaporative distlllation and are not optimized. The unrearranged mixed ortho ester of 4 and 5 (IO-20%) and tarry polymers comprise the remainder of the mass balance;. no other characterizable products were isolated. (c) Additional 'H NMR data (CC14): 6b, 6 1.15 (t, J = 7 Hz), 1.23 (t, J = 7 Hz), and 1.46 (d, J = 7 Hz, CH3CH) (total 9 H), 3.71 (AB. J = 16 Hz, Au = 0.40 ppm, ArCH2C02Et) and 3.95-4.40 (m) (total 7 H), 7.20-7.40 (m. 4 H); 6c, 1.08-1.36 (two overlapping t) and 1.28 (s)(total 12 H), 3.90-4.32 (m, 6 H), 7.38 (s,4 H). 'H NMR data (CDc13): 6a, 6 1.16 (t, J = 7 Hz) and 1.27 (t, J = 7 Hz) (total 6 H), 2.33 (s,3 H, p C Y A r ) , 3.67 (s,2 H, 3-indolyl-CH2C02Et),3.9-4.4 (two overlapping q), and 4.20 (s,2-indolyl-CH2C02Et) (total 6 H), 7.0-8.2 (m, 8 H);
0002-7863/78/lS00-4903$01 .OO/O
6b, 6 1.18 (t. J = 7 Hz, 3 H), 2.30 (s, 3 H. pCH3Ar), 3.66 (s,3-indolylCHzC02Et) and 3.72 (s, C02CH3) (total 5 H), 4.10 (q, J = 7 Hz, C02CH2) and 4.20 (s, 2-indolyl-CH2C02Me) (total 4 H), 7.1-8.2 (m, 8 H); 6c, 6 1.17 (t, J = 7 Hz) and 1.20 (t, J = 7 Hz) (total 6 H), 1.60 (d, J = 7 Hz, 2 H, CH3CH
